Survival, proliferation and differentiation of erythroid progenitor cells are sensitive to the local environment. Decreased oxygen tension decreased proliferation and increased fetal hemoglobin production, resulting in cytotoxicity at low oxygen tension. Erythropoietin treatment to augment hydroxyurea therapy in sickle cell patients was considered to increase fetal hemoglobin. However, we found that increasing erythropoietin level increased proliferation and hemoglobin positive cells without changes in fetal hemoglobin production, suggesting that while treatment with erythropoietin may increase red cell production, erythropoietin alone may not be sufficient to alter the hemoglobin program and induce fetal hemoglobin production. Increasing erythropoietin concentration in erythroid progenitor cell cultures also increases in glucose uptake. We also observed that increased hematocrit in mice treated with erythropoietin was accompanied by decrease blood glucose level and improved glucose tolerance, suggesting metabolic glucose response associated with increased erythropoietin stimulated erythropoiesis. This was seen in both male and female mice, although only male mice showed decreased body weight, fat mass and food intake with erythropoietin treatment, suggesting that erythropoietin stimulated glucose metabolism was independent of the erythropoietin response in white adipose tissue. Other changes in the bone marrow microenvironment have the potential to influence hematopoiesis and erythroid differentiation. Bone marrow fat can negatively regulate hematopoiesis and osteogenesis, and we observed a decrease in the number of bone marrow adipocytes as well as bone loss accompanying erythropoietin stimulated erythropoiesis in mice. Hydroxyurea is used as treatment in sickle cell disease to induce fetal hemoglobin and reduce the hemoglobin polymerization tendency in the red cell associated with sickle hemoglobin production. Hydroxyurea has also been suggested to increase nitric oxide, decrease corpuscular hemoglobin concentration and alter endothelial cell adhesion. In hydroxyurea treatment for hematological malignancies, we that the increase in angiogenic factors associated with granulocytes, CD34+ cells and bone marrow in patients with myeloproliferative neoplasms was decreased after hydroxyurea therapy suggesting possible decrease in associated angiogenesis may relate to prolonged survival.